Previous work in our laboratory provided evidence for the existence of an insulin sensitive glucoregulator center in the CNS. Exposing the CNS to insulin injected through the carotid artery, a decrease of the systemic plasma glucose concentration was observed. This was inhibited by intracarotid injection of atropine, or by cutting the vagus nerves prior to insulin injection. More recently we have observed similar decrease in hepatic venous plasma glucose concentration after stereotaxic microinjections of 10, 50 and 100 microunits of insulin into the ventromedial hypothalamic nuclei (VMN). The current project proposes to study the operating mechanism of the CNS glucoregulator by altering glucose utilization in the VMN with 2-deoxyglucose or with phlorizin and, in other experiments, by exposing this area to antagonists of neurotransmitters (atropine, phentolamine, propranolol) prior to stereotaxic microinjections of insulin. The effector mechanism will be studied in rats with experimentally impaired pancreatic endocrine function (i.e., in alloxanized or somatostatin pretreated rats). Finally, a search for other insulin responsive glucoregulator areas will be undertaken, using the methodology already established. In this search, emphasis will be on the periventricular regions (organum vasculosum, subfornical organ, and area postrema) which are known to be rich in insulin receptors, and which areas may have incomplete blood/ brain barrier function.